Traversing the cascade: urgent research priorities for implementing the 'treat all' strategy for children and adolescents living with HIV in sub-Saharan Africa

Children and adolescents living with HIV (CALHIV) in sub-Saharan Africa experience significant morbidity and alarmingly high mortality rates due to critical gaps in the HIV care cascade, including late diagnosis and initiation of treatment, as well as poor retention in care and adherence to treatment. Interventions to strengthen the adult HIV care cascade may not be as effective in improving the cascade for CALHIV, for whom specific strategies are needed. Particular attention needs to be paid to the contexts of sub-Saharan Africa, where more than 85% of the world's CALHIV live. Implementing the 'treat all' strategy in sub-Saharan Africa requires dedicated efforts to address the unique diagnosis and care needs of CALHIV, in order to improve paediatric and adolescent outcomes, prevent viral resistance and reduce the number of new HIV infections. We consider the UNAIDS 90-90-90 targets from the perspective of infants, children and adolescents, and discuss the key challenges, knowledge gaps and urgent research priorities for CALHIV in implementation of the 'treat all' strategy in sub-Saharan Africa

Immunological response to highly active antiretroviral therapy following treatment for prevention of mother to child transmission of HIV-1: a study in Côte d'Ivoire

<p>Abstract</p> <p>Background</p> <p>Information is currently limited on the long-term follow up of HIV-1 infected women who are on highly active antiretroviral therapy (HAART) that contains nevirapine and lamivudine and who were previously exposed to antiretroviral drugs for the prevention of mother to child transmission (PMTCT) of HIV.</p> <p>Methods</p> <p>We studied the 36-month immunological response to HAART in HIV-1 infected women in Côte d'Ivoire. The women were previously exposed to antiretroviral drug regimens for PMTCT, including single-dose nevirapine and/or short-course zidovudine with or without lamivudine. All HAART regimens included a non-nucleoside reverse transcriptase inhibitor.</p> <p>Results</p> <p>At 36 months: the median absolute increase in CD4+ T cell count was +359 cells/mm³(IQR: 210-466) in 200 women who had undergone 36-month follow-up visits; +359 cells/mm³(IQR: 222-491) in 88 women not exposed to PMTCT antiretrovirals; and +363 cells/mm³(IQR: 200-464) in 112 women exposed to at least one antiretroviral PMTCT regimen. Overall, 49 (19.8%) of the 247 women who initiated HAART met the immunological failure criteria at least once during follow up. The overall probability of immunological failure was 0.08 (95% CI: 0.12-0.15) at 12 months, and 0.21 (95% CI: 0.16-0.27) at 36 months. No difference was observed according to the presence or absence of resistance mutations to nevirapine or lamivudine in women tested at four weeks postpartum. In addition, at 36 months, 23% of women were lost to follow up, dead or had stopped their treatment.</p> <p>Conclusions</p> <p>A non-nucleoside reverse transcriptase inhibitor-based antiretroviral regimen, initiated a year or more after PMTCT exposure and that includes nevirapine, remains a good option for at least the first 36 months of treatment.</p

Effectiveness and safety of dolutegravir and raltegravir for treating children and adolescents living with HIV: a systematic review

INTRODUCTION: Globally about 1.7 million children were living with HIV in 2020. Two integrase strand transfer inhibitors, dolutegravir and raltegravir, are increasingly used in children. We conducted a systematic review to assess the effectiveness and safety of dolutegravir and raltegravir in children and adolescents living with HIV, aged 0–19 years. METHODS: Sources included MEDLINE, Embase, the Cochrane Library, clinical trial registries, abstracts from key conferences and reference list searching. Observational studies and clinical trials published January 2009–March 2021 were eligible. Outcomes included efficacy/effectiveness (CD4 counts and viral load) and/or safety outcomes (mortality, grade 3/4 adverse events and treatment discontinuation) through 6 months or more post-treatment initiation. Risk of bias was assessed using previously published tools appropriate for the study design. Narrative syntheses were conducted. RESULTS AND DISCUSSION: In total, 3626 abstracts and 371 papers were screened. Eleven studies, including 2330 children/adolescents, reported data on dolutegravir: one randomized controlled trial (RCT; low risk of bias), one single-arm trial (unclear risk of bias) and nine cohort studies (three low risk of bias, two unclear risk and four high risk). Ten studies, including 649 children/adolescents receiving raltegravir, were identified: one RCT (low risk of bias), one single-arm trial (low risk of bias) and eight cohort studies (four low risk of bias, three unclear risk and one high risk). Viral suppression levels in children/adolescents at 12 months were high (>70%) in most studies assessing dolutegravir (mostly second- or subsequent-line, or mixed treatment lines), and varied from 42% (5/12) to 83% (44/53) at 12 months in studies assessing raltegravir (mostly second- or subsequent-line). Across all studies assessing dolutegravir or raltegravir, grade 3/4 adverse events (clinical and/or laboratory) were reported in 0–50% of subjects, few resulted in discontinuation, few were drug related and no deaths were attributed to either drug. CONCLUSIONS: These reassuring findings suggest that dolutegravir and raltegravir are effective and safe as preferred regimens in children and adolescents living with HIV. With the rollout of dolutegravir in paediatric populations already underway, it is critical that data are collected on safety and effectiveness in infants, children and adolescents, including on longer-term outcomes, such as weight and metabolic changes

Time to First-Line ART Failure and Time to Second-Line ART Switch in the IeDEA Pediatric Cohort

BACKGROUND: Globally, 49% of the estimated 1.8 million children living with HIV are accessing antiretroviral therapy (ART). There are limited data concerning long-term durability of first-line ART regimens and time to transition to second-line. METHODS: Children initiating their first ART regimen between 2 and 14 years of age and enrolled in one of 208 sites in 30 Asia-Pacific and African countries participating in the Pediatric International Epidemiology Databases to Evaluate AIDS consortium were included in this analysis. Outcomes of interest were: first-line ART failure (clinical, immunologic, or virologic), change to second-line, and attrition (death or loss to program ). Cumulative incidence was computed for first-line failure and second-line initiation, with attrition as a competing event. RESULTS: In 27,031 children, median age at ART initiation was 6.7 years. Median baseline CD4% for children ≤5 years of age was 13.2% and CD4 count for those >5 years was 258 cells per microliter. Almost all (94.4%) initiated a nonnucleoside reverse transcriptase inhibitor; 5.3% a protease inhibitor, and 0.3% a triple nucleoside reverse transcriptase inhibitor-based regimen. At 1 year, 7.7% had failed and 14.4% had experienced attrition; by 5 years, the cumulative incidence was 25.9% and 29.4%, respectively. At 1 year after ART failure, 13.7% had transitioned to second-line and 11.2% had experienced attrition; by 5 years, the cumulative incidence was 31.6% and 25.9%, respectively. CONCLUSIONS: High rates of first-line failure and attrition were identified in children within 5 years after ART initiation. Of children meeting failure criteria, only one-third were transitioned to second-line ART within 5 years

Glob Health Action

Adolescents living with HIV are sexually active and engaged in risky sexual behaviors. Knowledge on how and to what extent adolescents in HIV care are affected by pregnancy is needed so as to adopt better preventive services. We estimated 4-year pregnancy incidence and correlates among HIV-infected female adolescents in HIV care in urban Côte d'Ivoire. We conducted retrospective analysis of a pediatric prospective cohort of the International epidemiological Databases to Evaluate AIDS (IeDEA) West Africa Collaboration. Female patients with confirmed HIV infection aged 10-19 years, having at least one clinical visit in 2009 to health facilities participating in the pediatric IeDEA West African cohort in Abidjan, Côte d'Ivoire, were included. Data on incident pregnancies were obtained through medical records and interviews with health professionals. Pregnancy incidence rate was estimated per 100 person-years (PY). Poisson regression models were used to identify factors associated with the first pregnancy and provided incidence rate ratios (IRR) with 95% confidence intervals (CI). In 2009, 266 female adolescents were included, with a median age of 12.8 years (interquartile range, IQR: 10.0-15.0), CD4 cell counts of 506 cells/mm(3) (IQR: 302-737), and 80% on antiretroviral treatment. At the 48th month, 17 new pregnancies were reported after 938 PY of follow-up: 13 girls had one pregnancy while 2 had two pregnancies. Overall incidence rate of pregnancy was 1.8/100 PY (95% CI: 1.1-2.9). High incidence was observed among those aged 15-19 years: 3.6/100 PY (95% CI: 2.2-5.9). Role of maternal death in the risk of pregnancy was at the limit of statistical significance (adjusted IRR: 3.1, 95% CI: 0.9-11.0; ref. non-maternal orphans). Incidence of pregnancy among HIV-infected adolescents in care aged 15-19 years reached a level observed in adult cohorts in Sub-Saharan Africa. Health personnel in pediatric care have to intensify their efforts to provide more realistic and age-adapted reproductive health services to meet the needs of adolescent patients already confronting issues of sexuality. Vulnerability of maternal orphans merits further investigation

Global variations in pubertal growth spurts in adolescents living with perinatal HIV

Objective: To describe pubertal growth spurts among adolescents living with perinatally-acquired HIV (ALWPHIV) on antiretroviral therapy (ART)./ Design: Observational data collected from 1994–2015 in the CIPHER global cohort collaboration./ Methods: ALWPHIV who initiated ART age <10 years with ≥4 height measurements age ≥8 were included. Super Imposition by Translation And Rotation (SITAR) models, with parameters representing timing and intensity of the growth spurt, were used to describe growth, separately by sex. Associations between region, ART regimen, age, height-for-age (HAZ), and BMI-for-age z-scores (BMIz) at ART initiation (baseline) and age 10 years and SITAR parameters were explored./ Results: 4,723 ALWPHIV were included: 51% from East and Southern Africa (excluding Botswana and South Africa), 17% Botswana and South Africa, 6% West and Central Africa, 11% Europe and North America, 11% Asia-Pacific, and 4% Central, South America, and Caribbean. Growth spurts were later and least intense in sub-Saharan regions. In females, older baseline age and lower BMIz at baseline were associated with later and more intense growth spurts; lower HAZ was associated with later growth spurts. In males, older baseline age and lower HAZ were associated with later and less intense growth spurts; however, associations between baseline HAZ and timing varied by age. Lower HAZ and BMIz at 10 years were associated with later and less intense growth spurts in both sexes./ Conclusions: ALWPHIV who started ART at older ages or already stunted were more likely to have delayed pubertal growth spurts. Longer-term follow-up is important to understand the impact of delayed growth.

18-Month Effectiveness of Short-Course Antiretroviral Regimens Combined with Alternatives to Breastfeeding to Prevent HIV Mother-to-Child Transmission

OBJECTIVE: We assessed the 18-month effectiveness of short-course (sc) antiretroviral peripartum regimens combined with alternatives to prolonged breastfeeding to prevent mother-to-child transmission (MTCT) of HIV-1 in Abidjan, Côte d'Ivoire. METHODOLOGY: HIV-1 infected pregnant women received from >/=32-36 weeks of gestation scZidovudine (ZDV)+/-Lamivudine (3TC)+single-dose Nevirapine (sdNVP) at delivery within the ANRS 1201/1202 DITRAME-Plus cohort (2001-2003). Neonates received a sdNVP+7-day ZDV prophylaxis. Two infant-feeding interventions were systematically offered free of charge: formula-feeding or exclusive shortened breastfeeding with early cessation from four months. The reference group was the ANRS 049a DITRAME cohort (1994-2000) exposed to scZDV from 36 weeks, then to prolonged breastfeeding. Pediatric HIV infection was defined by a positive plasma HIV-1 RNA at any age, or if aged >/=18 months, a positive HIV-1 serology. Turnbull estimates of cumulative transmission risks (CTR) and effectiveness (HIV-free survival) were compared by exposure group using a Cox model. FINDINGS: Among 926 live-born children enrolled, 107 (11.6%) were HIV-infected at 18 months. CTRs were 22.3% (95% confidence interval[CI]:16-30%) in the 238 ZDV long-term breastfed reference group, 15.9% (CI:10-27%) in the 169 ZDV+sdNVP shortened breastfed group; 9.4% (CI:6-14%) in the 195 ZDV+sdNVP formula-fed group; 6.8% (CI:4-11%) in the 198 ZDV+3TC+sdNVP shortened breastfed group, and 5.6% (CI:2-10%) in the 126 ZDV+3TC+sdNVP formula-fed group. Each combination had a significantly higher effectiveness than the ZDV long-term breastfed group except for ZDV+sdNVP shortened breastfed children, ranging from 51% (CI:20-70%) for ZDV+sdNVP formula fed children to 63% (CI:40-80%) for ZDV+3TC+NVPsd shortened breastfed children, after adjustment for maternal eligibility for antiretroviral therapy (ART), home delivery and low birth-weight. Substantial MTCT risk reductions are reachable in Africa, even in short-term breastfed children. The two sc antiretroviral combinations associated to any of the two infant feeding interventions, formula-feeding and shortened breastfeeding, reduce significantly MTCT with long-term benefit until age 18 months and without increasing mortality

Net survival of perinatally and postnatally HIV-infected children: a pooled analysis of individual data from sub-Saharan Africa

Background Previously, HIV epidemic models have used a double Weibull curve to represent high initial and late mortality of HIV-infected children, without distinguishing timing of infection (peri- or post-natally). With more data on timing of infection, which may be associated with disease progression, a separate representation of children infected early and late was proposed. Methods Paediatric survival post-HIV infection without anti-retroviral treatment was calculated using pooled data from 12 studies with known timing of HIV infection. Children were grouped into perinatally or post-natally infected. Net mortality was calculated using cause-deleted life tables to give survival as if HIV was the only competing cause of death. To extend the curve beyond the available data, children surviving beyond 2.5 years post infection were assumed to have the same survival as young adults. Double Weibull curves were fitted to both extended survival curves to represent survival of children infected perinatally or through breastfeeding. Results Those children infected perinatally had a much higher risk of dying than those infected through breastfeeding, even allowing for background mortality. The final-fitted double Weibull curves gave 75% survival at 5 months after infection for perinatally infected, and 1.1 years for post-natally infected children. An estimated 25% of the early infected children would still be alive at 10.6 years compared with 16.9 years for those infected through breastfeeding. Conclusions The increase in available data has enabled separation of child mortality patterns by timing of infection allowing improvement and more flexibility in modelling of paediatric HIV infection and surviva

18-month occurrence of severe events among early diagnosed HIV-infected children before antiretroviral therapy in Abidjan, Côte d'Ivoire: A cohort study

<p>Abstract</p> <p>Objective</p> <p>To assess the 18-month field effectiveness on severe events of a pediatric package combining early HIV-diagnosis and targeted cotrimoxazole prophylaxis in HIV-infected children from age six-week before the antiretroviral era, in Abidjan, Côte d'Ivoire.</p> <p>Methods</p> <p>Data from two consecutive prevention of HIV mother-to-child transmission programs were compared: the ANRS 1201/1202 Ditrame-Plus cohort (2001–2005) and the pooled data of the ANRS 049a Ditrame randomized trial and its following open-labeled cohort (1995–2000), used as a reference group. HIV-infected pregnant women ≥ 32–36 weeks of gestation were offered a short-course peri-partum antiretroviral prophylaxis (ZDV in Ditrame, and ZDV ± 3TC+single-dose (sd) NVP in Ditrame-Plus). Neonatal prophylaxis was provided in Ditrame-Plus only: 7-day ZDV and sdNVP 48–72 h after birth. A 6-week pediatric HIV-RNA diagnosis was provided on-line in the Ditrame-Plus while it was only oriented on clinical symptoms in Ditrame. Six-week HIV-infected children received a daily cotrimoxazole prophylaxis in Ditrame-Plus while no prophylaxis was provided in Ditrame. The determinants of severe events (death or hospitalization > 1 day) were assessed in a Cox regression model.</p> <p>Results</p> <p>Between 1995 and 2003, 98 out of the 1121 live-births were diagnosed as HIV-infected in peri-partum: 45 from Ditrame-Plus and 53 from Ditrame. The 18-month Kaplan-Meier cumulative probability of presenting a severe event was 66% in Ditrame-Plus (95% confidence interval [95%CI]: 50%–81%) and 77% in Ditrame (95%CI: 65%–89%), Log Rank test: p = 0.47. After adjustment on maternal WHO clinical stage, maternal death, 6-week pediatric viral load, birth-weight, and breastfeeding exposure, the 18-month risk of severe event was lower in Ditrame-Plus than in Ditrame (adjusted Hazard Ratio (aHR): 0.55, 95%CI: 0.3–1.1), although the difference was not statistically significant; p = 0.07). Maternal death was the only variable determinant of the occurrence of severe events in children (aHR: 3.73; CI: 2.2–11.2; p = 0.01).</p> <p>Conclusion</p> <p>Early cotrimoxazole from 6 weeks of age in HIV-infected infants seemed to reduce probability of severe events but the study lacked statistical power to prove this. Even with systematic cotrimoxazole prophylaxis, infant morbidity and mortality remained high pointing towards a need for early pediatric HIV-diagnosis and antiretroviral treatment in Africa.</p

IeDEA-WHO Research-Policy Collaboration: contributing real-world evidence to HIV progress reporting and guideline development.

Partnerships between researchers and policymakers can improve uptake and integration of scientific evidence. This article describes the research-policy partnership between the International epidemiology Databases to Evaluate AIDS (IeDEA) ( www.iedea.org) and the World Health Organization (WHO), which was established in 2014. IeDEA is an international research consortium, which analyses data on almost 2 million people living with HIV under care in routine settings in 46 countries in Asia-Pacific, the Caribbean, Central and South America, North America and sub-Saharan Africa. Five multiregional analyses were identified to inform the WHO on progress towards the second and third 90s of the 90-90-90 targets in adults and children: (i) trends in CD4 cell counts at the start of antiretroviral therapy (ART); (ii) delays from enrolment in HIV care to ART initiation; (iii) the impact of ART guideline changes; (iv) retention in care, mortality and loss to follow-up; and (v) viral suppression within the first 3 years after initiating ART. Results from these analyses were contributed to the 2015 and 2016 WHO global HIV progress reports, will contribute to the 2018 report, and were published in academic journals. The partnership has been mutually beneficial: discussion of WHO policy agendas led to more policy-framed, relevant and timely IeDEA research, and the collaboration provided the WHO with timely access to the latest data from IeDEA, as it was shared prior to peer-review publication